Science Made Simple

Learn » Drug Development » Turning on Cellular Garbage Disposals

Turning on Cellular Garbage Disposals

by | Sep 8, 2023 | Drug Development


Many drugs work by stopping overactive proteins that cause disease. The leukemia drug Gleevec, for example, is a small-molecule inhibitor (antagonist) of the protein Bcr-Abl, whose over-activity promotes excessive cell division. Humira treats a range of autoimmune diseases by stopping TNF-alpha, a protein that activates inflammation.

Such antagonists can be powerful. However, developing a strong inhibitor of a disease-associated protein is not always possible. And when scientists do develop them, resistance often emerges, rendering a drug ineffective.

What if, instead of merely inhibiting a protein, we could totally get rid of it? It turns out that our cells already have that ability. In this article, we look at a new class of drugs scientists are developing to take advantage of our bodies’ microscopic sanitation departments.


If allowed to accumulate, proteins can interfere with normal cell function. Therefore, all cells contain proteasomes, compartments that break apart unneeded or damaged proteins. Proteasomal degradation also provides a way to recycle the amino acid building blocks of proteins. Once a protein is broken down, a cell can use the leftover amino acid “bits” to rebuild new proteins.

Proteins are targeted for degradation through the action of E3 ligase. This enzyme attaches another protein, ubiquitin, to the targeted protein. Ubiquitin then guides the target into a proteasome, where it’s broken down. Scientists can activate our cellular garbage disposal to fight illness if they figure out how to “tag” disease-associated proteins with ubiquitin. Several companies are working on clever ways to do just that.


Researchers at Arvinas (New Haven, CT) are developing a platform to target disease-causing proteins based on ubiquitination/proteasome systems. The platform is dubbed PROTAC (Proteolysis-Targeting Chimera) and consists of “bifunctional small molecules” – which simultaneously bind to two different proteins.

With PROTAC, one end binds to the target, the other to E3 ligase. This interaction transfers the ubiquitin to the target protein for eventual disposal. PROTAC doesn’t necessarily have to recognize a specific part of the target, such as the active site of an enzyme. That allows researchers to focus on a wider range of proteins than possible with existing technologies, such as small molecule inhibitors, which must fit precisely in an enzyme’s active site to work.

Arvinas has released preclinical data suggesting that PROTAC successfully lowers levels of the protein BRD4 in lymphoma, multiple myeloma, and prostate cancer cells. Currently, Arvinas’ ARV-471 and ARV-110 are in Phase II  development. BRD4 plays a role in cell division, and mutated versions are associated with various cancers. In 2018, Arvinas announced collaborations with Pfizer and Genentech, which should speed the progress of getting these molecules to the clinic.

C4 Therapeutics (Cambridge, MA) is developing a similar small molecule platform that connects disease-associated proteins with cellular ubiquitination enzymes. Dubbed “degronimids,” the molecules are still in preclinical development. Their potential was recognized early on by Google-backed Calico. The two companies collaborated in 2017, aiming to address diseases of aging. As their collaboration period comes to an end this year, it will be intriguing to see the advancements they’ve made together and what the future holds for their partnership.

Kymera (Cambridge, MA) is also utilizing small molecules to activate target-specific proteasome degradation, focusing first on oncology and autoimmunity. Celgene (Summit, NJ) and vividion (La Jolla, CA) have been collaborating on an ambitious project aimed at discovering drugs that interact with the ubiquitin-proteasome system. This system plays a critical role in cellular protein degradation and has been a target for various therapeutic interventions. As the collaboration matures, the scientific community eagerly anticipates breakthroughs that could revolutionize treatments for a range of diseases.


It’s clear that many drug developers place great faith in tapping proteasome power to advance human health. In what could seem completely contradictory, other companies are taking the opposite approach: squelching the proteasome.

The process of apoptosis, or programmed cell death, occurs naturally in cells as a protective mechanism. For example, cells that sustain large amounts of DNA damage activate apoptosis to prevent them from seeding a tumor.

Many pharmaceutical companies are trying to co-opt apoptosis to treat cancer. One way to induce the process is to inhibit the action of proteasomes. The resulting buildup of damaged proteins signals the cell that something is seriously amiss, setting off cell death.

The FDA has approved Velcade, marketed by Takeda Oncology (originally Millennium Pharmaceuticals) (Cambridge, MA), to treat multiple myeloma. Krypolis, developed by Onyx (South San Francisco), is another proteasome inhibitor approved as a second-line treatment for multiple myeloma. Both are small-molecule drugs.

A better understanding of how our cells process unwanted proteins has opened up an entirely new approach to treating diseases. Manipulating the world’s tiniest garbage disposals may hold the key to healing otherwise untreatable conditions.


The exploration of cellular proteasomes as a novel approach to drug development is ushering in a new era of medical treatment. Companies like Arvinas, C4 Therapeutics, and Kymera are pioneering technologies that leverage the ubiquitin-proteasome system to degrade disease-associated proteins, offering a promising alternative to traditional small-molecule inhibitors that often face limitations like drug resistance. At the same time, the dual role of proteasomes—both as a mechanism for protein degradation and as a target for inducing apoptosis in cancer treatment—adds a layer of complexity and versatility to this emerging field. As we continue to unlock the secrets of these cellular garbage disposals, we may be opening the door to revolutionary treatments for a wide range of previously untreatable conditions.


1. What are proteasomes?

Proteasomes are cellular compartments that break down unneeded or damaged proteins. They act as the cell’s garbage disposal system, ensuring that proteins do not accumulate and interfere with normal cell function.

2. How do proteasomes work?

Proteins are targeted for degradation by an enzyme called E3 ligase, which attaches another protein, ubiquitin, to the targeted protein. This ubiquitin-tagged protein is then guided into the proteasome, where it is broken down.

3. What is PROTAC?

PROTAC (Proteolysis-Targeting Chimera) is a platform developed by Arvinas that uses bifunctional small molecules to target disease-causing proteins for degradation. One end of the molecule binds to the target protein, and the other end binds to E3 ligase, facilitating the degradation process.

4. Are there any drugs based on proteasome technology?

Yes, drugs like Velcade and Krypolis are proteasome inhibitors approved for treating multiple myeloma. On the other hand, drugs like ARV-471 and ARV-110 by Arvinas are in Phase II development and aim to leverage proteasomes for protein degradation.

5. Is proteasome-based treatment safe?

While the technology is promising, it is still in the experimental stage for many applications. Safety and efficacy are subject to ongoing clinical trials.

6. What diseases could potentially be treated with proteasome-based drugs?

The technology can potentially treat a wide range of diseases, including various types of cancer, autoimmune diseases, and even diseases of aging.

Explore a range of in-depth biotech courses designed to deepen your
understanding of key principles and applications in the field. Enroll today
Author: Emily Burke, PhD
Editor: Sarah Van Tiems, MS
Scientific Review: Tahir Hayat, MS


Submit a Comment

Your email address will not be published. Required fields are marked *

Drug Discovery of Biologics